Anthracycline antibiotics including doxorubicin and daunorubicin are important chemotherapeutic agents in the treatment of a broad spectrum of neoplastic conditions. While daunorubicin (1) is clinically used mainly against acute childhood and adult leukemias, doxorubicin (2), also known as adriamycin, has the widest spectrum of antitumor activity of all chemotherapeutic agents (Weiss, R. B., Sarosy, G., Clagett-Carr, K., Russo, M. and Leyland-Jones, B., Cancer Chemother. Pharmacol., 18, 185-197, 1986; Arcamone, F., Doxorubicin, Academic Press, New York, 1980). ##STR1##
The usefulness of known anthracycline antibiotics is compromised by dose limiting toxicities such as myelosuppression (Crooke, S. K., Anthracyclines; Current Status and New Developments, Academic Press, New York 1980) and cardiotoxicity (Olson, R. D. et al, Proc. Natl. Acad. Sci., USA 85 3585-3589, 1988 and references therein) as well as the resistance from treated tumors (Mimnaugh, E. G. et al, Cancer Research, 49, 8-15, 1989; McGrath, T. et al, Biochemical Pharmacology, 38 497-501, 1989). In view of the proven effectiveness of known anthracyclines in the treatment of cancer, efforts have been undertaken to develop anthracycline analogs with either an improved therapeutic index or with reduced cross-resistance.
Several thousands of anthracycline derivatives have been obtained either from streptomyces biosynthesis or via the semisynthetic modification of known natural anthracycline antibiotics (Arcamone, F., Doxorubicin, Academic Press, New York 1980; Thomson, R. H., Naturally Occurring Quinones III: Recent Advances, Chapman and Hall, New York 1987; Anthracyclines: Current Status and New Developments, Academic Press, New York, 1980; Brown, J. R. and Iman, S. H., Recent Studies on Doxorubicin and its Analogues, Prog. Med. Chem. 21 170-236, 1984; Brown, J. R. Adriamycin and Related Anthracycline Antibiotics, Prog. Med. Chem., 15, 125-164, 1978). The majority of known anthracyclines show two types of structural differences: (i) the substitution pattern of the aglycone tetracyclic ring system, and (ii) the structure and number of glycosides attached at C-7 or C-10 (doxorubicin numbering). Some examples of the structural diversity of anthracycline antibiotics are shown in FIG. 1. ##STR2##
In contrast to the great number of derivatives obtained from these two kinds of structural modifications, there has been little effort towards the synthesis and biological evaluation of ring-A heteroanthracycline derivatives. Some 9-oxa-heteroanthracyclines (3-5) were prepared by Koch et al but antitumor activity was not significant (Heterocycles, 26(2), 341-5, 1987; Heterocycles 26(4), 879-82, 1987). Mitsher et al found that N-(trifluoroacetyl)-4-demethoxy-9-azadaunorubicin (6) had no antitumor activity (J. Med. Chem., 29(7), 1277-81, 1986). ##STR3##
Pyranonaphthoquinones such as nanaomycin A (7) and kalafungin (8) occur naturally and show potent antibacterial as well as antifungal activity (Moore, H. W. and Czerniak, R., Medicinal Research Reviews, 1(3), 249-280, 1981 and references therein). Granaticin (9) has been reported to show antitumor activity (Chang, C. J., Floss, H. G., Soong, P. and Chang, C. T., J. Antibiot., 28, 156, 1975). ##STR4##